1. Field of the Invention
The present invention concerns antitumor compounds. More particularly, the invention provides novel paclitaxel derivatives, pharmaceutical formulations thereof, and their use as antitumor agents.
2. Background Art
Paclitaxel is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia and the active constituent of the anticancer agent TAXOL(copyright). It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is used clinically against a number of human cancers. It is an important cancer agent both therapeutically and commercially. Numerous clinical trials are in progress to expand the increase the utility of this agent for the treatment of human proliferative diseases. The results of TAXOL(copyright) clinical studies have been reviewed by numerous authors. A very recent compilation of articles by a number of different authors is contained in the entire issue of Seminars in Oncology 1999, 26 (1, Suppl 2). Other examples are such as by Rowinsky et al. in TAXOL(copyright): A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: pp 1247-1259, 1990; by Rowinsky and Donehower in xe2x80x9cThe Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics,xe2x80x9d Pharmac. Ther., 52:35-84,1991; by Spencer and Faulds in xe2x80x9cPaclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer,xe2x80x9d Drugs, 48 (5) 794-847,1994; by K. C. Nicolaou et al. in xe2x80x9cChemistry and Biology of TAXOL(copyright),xe2x80x9d Angew. Chem., Int. Ed. Engl., 33: 15-44, 1994: by F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber. J. A. Ajani, V. Valero in the book xe2x80x9cTaxane Anticancer Agents Basic Science and Current Statusxe2x80x9d edited by Gunda 1. Georg, Thomas T. Chen, lwao Ojima, and Dolotrai M. Vyas, 1995, American Chemical Society, Washington, D.C., 31-57; by Susan G. Arbuck and Barbara Blaylock in the book xe2x80x9cTAXOL(copyright) Science and Applicationsxe2x80x9d edited by Mathew Suffness, 1995, CRC Press Inc., Boca Raton, Fla., 379-416; and also in the references cited therein.
A semi-synthetic analog of paclitaxel named docetaxel has also been found to have good antitumor activity and is the active ingredient of the commercially available cancer agent TAXOTERE(copyright). See, Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substitutents and Variable C-2xe2x80x2 Configurations, J. Med. Chem., 34, pp 1176-1184 (1991); Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity, J. Med. Chem., 34. pp 992-998 (1991). A review of the clinical activity of TAXOTERE(copyright) by Jorge E. Cortes and Richard Pazdur has appeared in Journal of Clinical Oncology 1995, 13(10), 2643 to 2655. The structures of paclitaxel and docetaxel are shown below along with the conventional numbering system for molecules belonging to the class; such numbering system is also employed in this application. 
paclitaxel (TAXOL(copyright)): R=Ph; Rxe2x80x2=acetyl
docetaxel (TAXOTERE(copyright)): R=t-butoxy; Rxe2x80x2=hydrogen
The intention of this invention is to provide new 7-deoxy taxane analogs with useful anticancer properties. Some of the background art pertaining to this invention are shown below.
Several Publications have described the synthesis or attempted synthesis of the 7-deoxy analog of paclitaxel. These are:
Chen, Shu Hui; Huang, Stella; Kant, Joydeep; Fairchild, Craig Wei, Jianmei; Farina, Vittorio. xe2x80x9cSynthesis of 7-deoxy- and 7,10-dideoxytaxol via radical intermediatesxe2x80x9d. J. Org. Chem., 58(19). 5028-9, 1993.
Chaudhary, Ashok G.; Rimoldi, John M.; Kingston, David G. I. xe2x80x9cModified taxols. 10. Preparation of 7-deoxytaxol, a highly bioactive taxol derivative, and interconversion of taxol and 7-epi-taxolxe2x80x9d. J. Org. Chem., 58(15), 3798-9, 1993.
Matovic, Radomir; Saicic, Radomir N. xe2x80x9cAn efficient semisynthesis of 7-deoxypaclitaxel from taxinexe2x80x9d. Chem. Commun. (Cambridge). (16), 1745-1746, 1998.
A U.S. patent (U.S. Pat. No. 5,478,854) covering certain deoxy taxanes issued on Dec 26th 1995 by Farina et. al.
A published PCT international application (WO 94/17050) from Holton et. al. discloses 7-deoxy taxane derivatives. Other than actual supporting examples already claimed in the above mentioned U.S. patent, this application discloses many multitudes of hypothetical 7-deoxy taxane analogs with no indication of which compounds would really be useful. This application also does not provide details of the preparation of any C-7 deoxy taxanes which are not covered by the above mentioned U.S. patent. Corresponding U.S. Pat. No. 5,271,268 to Holton et al was granted.
An issued U.S. patent (U.S. Pat. No. 5773461) by Wittman et. al. claims 7-deoxy taxane analogs with unique functional groups at the 6 position as antitumor agents.
A published PCT application (WO 9828288) by Staab et. al. published Jul. 2, 1998, corresponding to U.S. Pat. No. 5,977,386 granted Nov. 2, 1999, describes C-7 deoxy taxanes with thio substituents at the 6 position.
A published PCT application (WO 9838862) by Wittman et. al. published Sep. 11, 1998, corresponding to U.S. Pat. No. 5,912,264 granted Jun. 15, 1998, describes C-7 deoxy taxanes with halogen or nitro substituents on C-6.
Nondeoxy analogs with a 3xe2x80x2 furyl amide substituent on the sidechain have appeared in both the patent (U.S. Pat. No. 5227,400 and U.S. Pat. No. 5,283,253) and chemistry literature Georg, Gunda I.; Harriman, Geraldine C. B.; Hepperle, Michael; Clowers, Jamie S.; Vander Velde, David G.; Himes, Richard H. Synthesis, Conformational Analysis, and Biological Evaluation of Heteroaromatic Taxanes. J. Org. Chem. (1996), 61(8), 2664-76. Importantly, we are unaware of any reports describing the synthesis of a 7-deoxy analog with this 3xe2x80x2N furoylamide sidechain or any of their novel, useful anticancer properties such as those described by this invention.
Hydroxylation of the 3xe2x80x2 sidechain phenyl group of paclitaxel has been reported to lead to reduced potency and thus has been inferred to result in less activity as discussed in the following examples: Wright, M.; Monsarrat, B.; Royer, I.; Rowinsky, E. K.; Donehower, R. C.; Cresteil, T.; Guenard, D. Metabolism and pharmacology of taxoids. Pharmacochem. Libr. (1995), Volume Date 1995, 22 131-64; Sparreboom, Alexander; Huizing, Manon T.; Boesen, Jan J. B.; Nooijen, Willem J.; van Tellingen, Olaf; Beijnen, Jos H. Isolation, purification, and biological activity of mono- and dihydroxylated paclitaxel metabolites from human feces. Cancer Chemother. Pharmacol. (1995). 36(4), 299-304.
Monsarrat, Bernard; Mariel, Eric; Cros, Suzie; Gares, Michele, Guenard, Daniel; Gueritte-Voegelein, Francoise; Wright, Michel. Taxol metabolism. Isolation and identification of three major metabolites of taxol in rat bile. Drug Metab. Dispos. (1990), 18(6), 895-901.
The synthetic preparation of the parahydroxylated 3xe2x80x2phenyl metabolite has been described in the literature. Park, Haeil; Hepperle, Michael; Boge, Thomas C.; Himes, Richard H.; Georg, Gunda I. Preparation of Phenolic Paclitaxel Metabolites. J. Med. Chem. (1996), 39(14), 2705-2709. We are not aware of any published reports of synthetic analogs with phydroxy phenyl 3xe2x80x2 sidechains that are purported to have activity advantages.
However, one reference in the patent literature mentions in passing that the para hydroxy phenyl metabolite might have an improved therapeutic index despite reduced potency and thus it""s formation in vivo may be fortuitous. Broder et.al. PCT Int. Appl. WO 9715269 published May 1, 1997.
However, this patent does not describe the synthesis or administration of para-hydroxyphenyl taxanes nor any actual efficacy results. Thus, the art clearly shows that the phydroxy phenyl sidechain analog of paclitaxel will be less potent than the parent drug. Most significantly, we are unaware of any prior art which describes the synthesis of novel 7-deoxy taxanes with a 3xe2x80x2parahydroxyphenyl containing sidechain or which describes their novel and unexpected antitumor properties such as those contained in this application.
Both TAXOL(copyright) and TAXOTERE(copyright) have no oral activity in human or animal models as mentioned in the following prior art on taxanes and modulators. Methods for administering taxanes in the presence of modulators have been been reported to increase the amount of taxanes in the plasma after oral administration: Terwogt, Jetske M. Meerum; Beijnen, Jos H.; Ten Bokkel Huinink, Wim W.; Rosing, Hilde; Schellens, Jan H. M. Co-administration of cyclosporin enables oral therapy with paclitaxel. Lancet (1998), 352(9124), 285.
Hansel, Steven B. A method of making taxanes orally bioavailable by coadministration with cinchonine. PCT Int. Appl. WO 9727855 published Aug. 7, 1997.
Broder, Samuel; Duchin, Kenneth L.; Selim, Sami. Method and compositions for administering taxanes orally to human patients using a cyclosporin to enhance bioavailability. PCT Int. Appl. WO 9853811 published Dec. 3, 1998. These reports contain no antitumor efficacy data but the presence of taxanes in the plasma is extrapolated to show their potential for anaticancer utility.
At least one report of oral activity of taxane analogs or prodrugs in preclinical animal models has appeared in the prior art: Scola, Paul M.; Kadow, John F.; Vyas, Dolatrai M. Preparation of paclitaxel prodrug derivatives. Eur. Pat. Appl. EP 747385 published Dec. 11, 1996. The oral bioavailability of the prodrug which had oral efficacy was not disclosed and no further reports of these compounds progressing to man have appeared. Thus it is clear that taxanes with both good oral bioavailability and good oral efficacy are at minimum, exceedingly rare. There are no such compounds which have been reported to demonstrate both oral bioavailbility and anticancer activity in man.
Several Publications have described the synthesis or attempted synthesis of some 7-deoxy taxane analogs and these are included only because they are additional references in the area of 7-deoxy taxanes.
Chen, Shu Hui; Huang, Stella; Kant, Joydeep; Fairchild, Craig; Wei, Jianmei; Farina, Vittorio. xe2x80x9cSynthesis of 7-deoxy- and 7,10-dideoxytaxol via radical intermediatesxe2x80x9d. J. Org. Chem., 58(19), 5028-9, 1993.
Chaudhary, Ashok G.; Rimoldi, John M.; Kingston, David G. I. xe2x80x9cModified taxols. 10. Preparation of 7-deoxytaxol, a highly bioactive taxol derivative, and interconversion of taxol and 7-epi-taxolxe2x80x9d. J. Org. Chem., 58(15). 3798-9, 1993.
Matovic, Radomir; Saicic, Radomir N. xe2x80x9cAn efficient semisynthesis of 7-deoxypaclitaxel from taxinexe2x80x9d. Chem. Commun. (Cambridge), (16), 1745-1746, 1998.
Chen, Shu Hui; Wei, Jian Mei; Vyas, Dolatrai M.; Doyle, Terrence W.; Farina, Vittorio. xe2x80x9cA facile synthesis of 7,10-dideoxytaxol and 7-epi-10-deoxytaxolxe2x80x9d. Tetrahedron Lett., 34(43), 6845-8, 1993.
Poujol, Helene; Al Mourabit, Ali; Ahond, Alain; Poupat, Christiane; Potier, Pierre. xe2x80x9cTaxoids: 7-dehydroxy-10-acetyldocetaxel and novel analogs prepared from yew alkaloidsxe2x80x9d. Tetrahedron, 53(37), 12575-12594, 1997.
Poujol, Helene; Ahond, Alain; Mourabit, Ali Al; Chiaroni, Angele; Poupat, Christiane; Potier, Claude Riche Et Pierre xe2x80x9cTaxoids: novel 7-dehydroxydocetaxel analogs prepared from yew alkaloidsxe2x80x9d. Tetrahedron, 53(14), 5169-5184, 1997.
Wiegerinck, Peter H. G.; Fluks, Lizette; Hammink, Jeannet B.; Mulders, Suzanne J. E.; de Groot, Franciscus M. H.; van Rozendaal, Hendrik L. M.; Scheeren, Hans W. xe2x80x9cSemisynthesis of Some 7-Deoxypaclitaxel Analogs from Taxine Bxe2x80x9d. J. Org. Chem., 61(20), 7092-7100, 1996.
Magnus, Philip; Booth, John; Diorazio, Louis; Donohoe, Timothy; Lynch, Vince; Magnus, Nicholas; Mendoza, Jose; Pye, Philip; Tarrant, James. xe2x80x9cTaxane diterpenes. 2: Synthesis of the 7-deoxy ABC taxane skeleton, and reactions of the A-ringxe2x80x9d. Tetrahedron, 52(45), 14103-14146, 1996.
Magnus, Philip; Booth, John; Diorazio, Louis; Donohoe, Timothy; Lynch, Vince; Magnus, Nicholas; Mendoza, Jose; Pye, Philip; Tarrant, James. xe2x80x9cTaxane diterpenes. 2: Synthesis of the 7-deoxy ABC taxane skeleton and reactions of the A-ringxe2x80x9d. Tetrahedron, 52(45), 14103-14146, 1996.
Tarrant, James Giles. xe2x80x9cStudies directed towards the total synthesis of 7-deoxytaxol: synthesis of the tricyclic core of taxolxe2x80x9d. (1995), 303 pp. CAN 125:168367; AN 1996:406672 CAPLUS.
This invention relates to novel antitumor compounds represented by formula I, or pharmaceutical salts thereof 
wherein R1 is xe2x80x94CORz in which Rz is ROxe2x80x94, R, or heteroaryl, with the proviso that Rz must be heteroaryl unless either (1) Rg is Rk or R2 is xe2x80x94OCORb, or (2) Rg is Rk and R2 is xe2x80x94OC(O)Rb;
Rg is C3-6 alkyl, C3-6 alkenyl, C3-6 alkynyl C3-6 cycloalkyl, Rk, or a radical of the formula xe2x80x94Wxe2x80x94Rx in which W is a bond, or xe2x80x94(CH2)txe2x80x94, in which t is one or 2;
Rx is phenyl or heteroaryl, and furthermore Rx can be optionally substituted with one to three same or different C1-6alkyl, C1-6alkoxy, halogen or xe2x80x94CF3 groups;
Rk is a radical of the formula xe2x80x94Wxe2x80x94Rs in which W is a bond, or xe2x80x94(CH2)txe2x80x94, in which t is one or 2; and Rs is phenyl substituted with hydroxy;
R2 is xe2x80x94OCOR, H, OH, xe2x80x94OR, xe2x80x94OSO2R, xe2x80x94OCONRoR, xe2x80x94OCONHR, xe2x80x94OCOO(CH2)tR, xe2x80x94OCOOR, orxe2x80x94OCORb;
R and Ro are independently C1-6 alkyl, C3-6 cycloalkyl, benzyl, or phenyl, optionally substituted with either one hydroxy group or with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or xe2x80x94CF3 groups; and
Rb is -morpholino, -nheptyl, xe2x80x94CH2OPh,xe2x80x94(2-nitrophenyl), xe2x80x94CHxe2x95x90CHPhenyl or xe2x80x94(2-aminophenyl).
Another aspect of the present invention provides a method for inhibiting tumor in a mammalian host which comprises administering to said mammalian host an antitumor effective amount of a compound of formula I. The method of administration may be oral or intravenous or any other suitable route.
Yet, another aspect of the present invention provides a pharmaceutical formulation which comprises an antitumor effective amount of a compound of formula I in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
Yet, another aspect of the present invention provides a process for preparing 7-deoxy taxanes or baccatins by hydrogneation of the corresponding 6,7-olefin taxane intermediates.
In the application, unless otherwise specified explicitly or in context, the following definitions apply. In this application, the symbols once defined retain the same meaning throughout the application, until they are redefined.
The numbers in the subscript after the symbol xe2x80x9cCxe2x80x9d define the number of carbon atoms a particular group can contain. For example xe2x80x9cC1-6 alkylxe2x80x9d means a straight or branched saturated carbon chain having from one to six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl, and n-hexyl. Depending on the context, xe2x80x9cC1-6 alkylxe2x80x9d can also refer to C1-6alkylene which bridges two groups; examples include propane-1,3-diyl, butane-1,4-diyl, 2-methyl-butane-1,4-diyl, etc. xe2x80x9cC2-6 alkenylxe2x80x9d means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from two to six carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. Depending on the context, xe2x80x9cC2-6 alkenylxe2x80x9d can also refer to C2-6 alkenediyl which bridges two groups; examples include ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl, 2-hexene-1,6-diyl, etc. xe2x80x9cC2-6 alkynylxe2x80x9d means a straight or branched carbon chain having at least one carbon-carbon triple bond, and from two to six carbon atoms. examples include ethynyl, propynyl, butynyl, and hexynyl. As used herein t-butyloxy and t-butoxy are used interchangeably.
xe2x80x9cArylxe2x80x9d means aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and naphthyl. xe2x80x9cSubstituted arylxe2x80x9d means aryl independently substituted with one to five (but preferably one to three) groups selected from C1-6 alkanoyloxy, hydroxy, halogen, C1-6 alkyl, trifluoromethyl, C1-6 alkoxy, aryl, C2-6 alkenyl, C1-6 alkanoyl, nitro, amino, cyano, azido, C1-6 alkylamino, di-C1-6 alkylamino, and amido. xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine, and iodine.
xe2x80x9cHeteroarylxe2x80x9d means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, and like rings
xe2x80x9cHydroxy protecting groupsxe2x80x9d include, but are not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, 1-methyl-1-methoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl ether, dialkyl alkoxy silyl ethers such as diisopropyl methoxy silyl ethers; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, benzyl, and p-nitrophenyl. Additional examples of hydroxy protecting groups may be found in standard reference works such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., 1999, John Wiley and Sons, and McOmie; and Protective Groups in Organic Chemistry, 1975, Plenum Press.
xe2x80x9cPhxe2x80x9d means phenyl; xe2x80x9ciprxe2x80x9d means isopropyl;
The substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and moieties described herein, may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.
A preferred embodiment are compounds I, or pharmaceutically acceptable salts thereof in which R2 is xe2x80x94OC(O)Rb; and Rg is phenyl, 2-furyl, 2-thienyl C3-6 alkyl, C3-6 alkenyl, C3-6 cycloalkyl,or Rs; where t=0 and Rs is parahydroxyphenyl; and Rz is tBuOxe2x80x94, phenyl, or 2-Furyl.
Another preferred embodiment are compounds I, or pharmaceutically acceptable salts thereof in which R2 is xe2x80x94OCOR, H, OH, xe2x80x94OR, or xe2x80x94OCOOR; and Rg is Rs; and Rz is C1-6alkyloxy, phenyl, or heteroaryl.
An even more preferred embodiment are compounds I, or pharmaceutically acceptable salts thereof in which R2 is hydrogen, hydroxy, or acetyloxy; Rg is parahydroxyphenyl; and R1 is C3-6alkyloxycarbonyl.
Another preferred embodiment are compounds I, or pharmaceutically acceptable salts thereof in which Rz is 2-furyl, 3-furyl, 2-thienyl, or 3-thienyl; R2 is hydrogen, hydroxy or acetyloxy; and Rg is phenyl, 2-furyl, 2-thienyl C3-6 alkyl, C3-6 alkenyl, C3-6 cycloalkyl, or Rk where t=0 and Rs is parahydroxyphenyl;
A most preferred embodiment are compounds I, or pharmaceutically acceptable salts thereof in which Rz is 2-furyl or 3-furyl; and R2 is acetyloxy; and Rg is phenyl, C3-6 alkyl, or C3-6 cycloalkyl;
The new products that have the general formula I display a significant inhibitory effect with regard to abnormal cell proliferation, and have therapeutic properties that make it possible to treat patients who have pathological conditions associated with an abnormal cell proliferation. The pathological conditions include the abnormal cellular proliferation of malignant or non-malignant cells in various tissues and/or organs, including, non-limitatively, muscle, bone and/or conjunctive tissues; the skin, brain, lungs and sexual organs; the lymphatic and/or renal system; mammary cells and/or blood cells; the liver, digestive system, and pancreas; and the thyroid and/or adrenal glands. These pathological conditions can also include psoriasis: solid tumors; ovarian, breast, brain, prostate, colon, stomach, kidney, and/or testicular cancer, Karposi""s sarcoma; cholangiocarcinoma; choriocarcinoma: neuroblastoma; Wilm""s tumor, Hodgkin""s disease; melanomas; multiple myelomas; chronic lymphocytic leukemias; and acute or chronic granulocytic lymphomas. The novel products in accordance with the invention are particularly useful in the treatment of non-Hodgkin""s lymphoma, multiple myeloma, melanoma, and ovarian, urothelial, oesophageal, lung, and breast cancers. The products in accordance with the invention can be utilized to prevent or delay the appearance or reappearance, or to treat these pathological conditions. In addition, the compounds of formula I are useful in treating and/or preventing polycystic kidney diseases (PKD) and rheumatoid arthritis. The compounds of this invention may also be useful for the treatment of Alzheimer""s disease. While some of the products of general formula I are of interest due to advantages over commercial taxanes following iv administration others are of interest due to their unique properties after oral administration.
The compounds of this invention can be made by techniques from the conventional organic chemistry repertoire. Schemes I-V, which depict processes that compounds within the scope of formula I can be made, are only shown for the purpose of illustration and are not to be construed as limiting the processes to make the compounds by any other methods.
A compound of formula I may be produced by the processes as depicted in Schemes I-IV which follow. The methods can be readily adapted to variations in order to produce compounds within the scope of formula but not specifically disclosed. Further variations of the methods to produce the same compounds in somewhat different fashion will also be evident to one skilled in the art.
One of the ways the compounds of this invention can be made is by the general method which shown is Scheme I. In Step (a) of the scheme, azetidinone IV is reacted with a compound of formula II (a baccatin III derivative(copyright). The general class of azetidinones (xcex2-lactams) of formula IV are well known. Methods for preparing suitably substituted xcex2-lactams can be found in U.S. Pat. No. 5,175,315, European patent application 0 590 267 A2, the other U.S. patents or literature mentioned above, or references therein by Ojima et al. in Tetrahedron, 48, No. 34, pp 6985-7012 (1992); Journal of Organic Chemistry, 56, pp 1681-1683 (1991); and Tetrahedron Letters, 33. No. 39, pp 5737-5740 (1992); by Brieva et al. in J. Org. Chem., 58, pp 1068-1075; by Palomo et al. in Tetrahedron Letters, 31, No. 44, pp 6429-6432 (1990); and in Rey, Allan W.; Droghini, Robert; Douglas, James L.; Vemishetti, Purushotham; Boettger, Susan D.; Racha, Saibaba; Dillon, John L. Can. J. Chem. 72(10), 2131-6 (1994).
All disclosures are herein incorporated by reference in their entirety. The methods that can be adapted to variations in order to produce other azetidinones within the scope of formula IV, but not specifically disclosed herein or in the above references or reported elsewhere, will be obvious to anyone skilled in the art.
The baccatin III derivatives (II) can be attached to a sidechain using any of the methodology which is now already well known in the art. The many references cited in this invention disclosure and Tetrahedron, 48, No. 34, pp 6985-7012 (1992) describe processes whereby the class of azetidinones of formula IV are reacted with (C)13-hydroxy group of baccatin III derivatives or metal alkoxide thereof to afford taxane analogues with a variety of (C)13-side chains. In Step (a) of Scheme I, it is advantageous to convert the hydroxy group on the (C)13-carbon into a metal alkoxide before the coupling. The formation of a desired metal alkoxide may be done by reacting a compound of formula II with a strong metal base, such as lithium diisopropylamide, C1-6 alkyllithium, lithium bis(trimethylsilyl)amide, phenyllithium, sodium hydride, potassium hydrides lithium hydride, or the like base. For example when lithium alkoxide is desired, a compound of formula II may be reacted with n-butyllithium in an inert solvent such as tetrahydrofuran. For examples of attachment of substituted baccatins with a suitably substituted lactam via the method of Holton see U.S. Pat. No. 5,175,315; U.S. Pat. No. 5,466,834; U.S Pat. No. 5,229,526; U.S. Pat. No. 5,274,124; U.S. Pat. No. 5,243,045; U.S. Pat. No. 5,227,400; U.S. Pat. No. 5,336,785, and U.S. Pat. No. 5,254,580, U.S. Pat. No. 5,294,637, or EP 0 590 267 A2. Some examples of using xcex2-lactams to prepare other substituted taxane derivatives are n PCT WO94/14787. This patent also describes an alternative method for attaching substituted isoserine sidechains to substituted baccatins which would be applicable for the compounds of this invention. This same alternate method is described in another publication by Kingston et. al. Tetrahedron Lett. (1994), 35(26), 4483-4. Further information on alternative methods to attach sidechains to baccatins are contained in Thottathil, et.al Eur. Pat. AppI. EP 735036 published Oct. 2, 1996. 
The numbering on baccatin III derivative of formula II as used in this application is as follows: 
As used herein, R3 is a conventional hydroxy protecting group. Conventional hydroxy protecting groups are moieties which can be employed to block or protect a hydroxy function, and they are well known to those skilled in the art. Preferably, said groups are those which can be removed by methods which result in no appreciable destruction to the remaining portion of the molecule. Examples of such readily removable hydroxy protecting groups include chloroacetyl, methoxymethyl, 1-methyl-1-methoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, and t-butyidimethylsily ether, dialkyl alkoxy silyl ethers such as diisopropyl methoxy silyl ethers; 2,2,2-trichloroethyoxymethyl, 2,2,2-trichloroethyloxycarbonyl (or simply trichloroethyloxycarbonyl), benyloxycarbonyl and the like. Other suitable protecting groups which may be used are found in Chapter 2 of xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, 3rd Ed., by Theodora W. Greene and Peter G. M. Wuts (1999, John Wiley and Sons). A protecting group for formula IV compounds which has been used frequently in the literature is trialkylsilyl. In Step (b), the protecting group R3 is removed. If R3 equals triC1-6alkylsilyl, such as triethylsilyl, it can be removed with fluoride ion or with mineral acid in alcohol or acetonitrile. The removal with fluoride ion is conducted in an inert solvent such as tetrahydrofuran, methylene chloride, 1,4-dioxane, DMF, chloroform, or in the like solvent; and the reaction medium may be buffered with a weak acid such as acetic acid. An example of mineral acid is hydrochloric acid.
In compounds of this invention R2 may also be hydroxy. in compounds where R2 is hydroxy, a suitable protecting group must be utilized prior to sidechain cleavage or installed selectively on the C-10 hydroxy group prior to the coupling reaction. Trialkylsilyl, dialkylalkoxysilyl, CBz, or Troc protecting groups are suitable for this protecting group step and can be attached using methodology which is well known in the art. The protecting groups can ideally be removed simultaneously in step (b) or or in a separate deprotection step immediately preceding or following step (b).
The simple 7-deoxy baccatin core 11 can be prepared as described in the previously mentioned U.S. patent, U.S. Pat. No. 5,478,854 by Farina et al. Alternatively, the desired 7-deoxy baccatin core can be obtained using the chemistry shown in Scheme II. One likely example of a starting material for such a scheme would be paclitaxel in which R=benzoyl, Rg=phenyl and R2=acetoxy.
As shown in Scheme II, the starting material is a known taxane analog. The 2xe2x80x2 hydroxy group of a taxane analog with an intact sidechain is suitably protected to leave the most reactive hydroxy group at C-7. Compound 1 in Scheme I is protected at the 2xe2x80x2 hydroxy group at the sidechain. Step c describes the protection of the 2xe2x80x2 hydroxy group and uses as a 2xe2x80x2 tertbutyldimethylsilyl ether as an example. This protecting group is by now well known in the taxane art and has been described by several authors including Kingston and George. The example of compound 1 actually described utilizes this silyl protecting group at the 2xe2x80x2 position. Although this group is preferred, other protecting groups can be utilized. The preparation of intermediates arising from step c and step d are now well known in the art. The synthesis of the 7-trifluoromethanesulfonate (triflate) intermediate is shown in step d and is by now well known in the art. The preparation of 7-O triflates and their conversion into cyclopropane and olefin has been divulged by Johnson, R. A., et al., Taxol chemistry. 7-O-Triflates as precursors to olefins and cyclopropanes. Tetrahedron Letters, 1994. 35(43): p. 7893-7896 and by the same authors in WO 94/29288. The preferred synthesis utilizes DMAP as the base and triflic anhydride as the activating agent. Experimental details for the preparation of the olefin arising from step d are contained in U.S. Pat. No. 5,773,461. Hydrogenation of the olefin is carried out in step f to provide the 7-deoxy taxane intermediate. Many hydrogenation catalysts could be used for this hydrogenation reaction. Palladium based catalysts such as palladium on carbon or palladium hydroxide are suitable as well as Rhodium, Iridium, or platinum based catalysts. Solvents such as lower molecular weight alcohols are suitable for the reaction. Other inert solvents such as ethyl acetate used alone or as a cosolvent may also be utilized. The hydrogenation may be carried out from 1 to 5 atmospheres of hydrogen.
The preferred conditions are using 10% palladium on carbon catalyst, in ethanol under 65 PSI of hydrogen. The reaction may be run until theoretical amounts of hydrogen are consumed or more typically for excess time such as 48 h or longer, 
Removal of the 2xe2x80x2 TBS protecting group in these compounds as depicted by step g, is effected by triethylamine trihydrofluoride in THF solvent. Other fluoride sources could also be utilized. For example tetrabutyl ammonium fluoride, pyridinium hydrofluoride, potassium fluoride, or cesium fluoride may find utility. The potassium fluoride may be utilized in combination with a complexing agent such as 18-crown-6 or the like to aid in desilylation. A solvent such as acetonitrile is typically used under these conditions. Other conditions such as mild aqueous hydrochloric acid and a cosolvent such as acetonitrile or THF may be useful for deprotection. The same conditions work equally are applicable for other silicon based protecting groups.
Many of the schemes refer to a hydroxy protecting group, preferably a trialkylsilyl group. It is to be understood that hydroxy protecting group may be a carbonate or ester group xe2x80x94C(O)ORx or xe2x80x94C(O)Rx or substituted methyl, ethyl, or benzyl ethers. Thus when such a group is employed as a hydroxy protecting group, it may be removed to generate the free hydroxy protecting group. Many suitable protecting groups can be found in the book xe2x80x9cProtective Groups in Organic Synthesis: 3rd ed. by Thedora W. Greene and Peter G. M. Wuts Copyright 1999 by John Wiley and Sons Inc.xe2x80x9d
Thus deprotection as shown in step g generates compounds I from nondeoxy taxanes. However, removal of the sidechain as shown in step h provides baccatin intermediates II which can be attached to a novel sidechain as shown in Scheme I to generate additional novel compounds I.
As depicted in step h, reaction of I with tetrabutylammonium borohydride via the method of Magri et. al. in J. Org. Chem. 1986, 51, pp. 3239-3242 provides the substituted baccatin derivatives. For examples of the use of the Magri methodology to prepare other 7-substituted baccatins see U.S. Pat. No. 5,254,580 or U.S. Pat. No. 5,294.637.
Another aspect of the invention involves the synthesis of compounds I with novel substituents R2 at the C-10 position. As shown in Scheme III, these compounds can be prepared by selective hydrolysis of a C-10 acetyl group of compounds I to generate compounds IV. Alternatively, compounds IV can be directly prepared as described in Scheme I by utilizing a C-10 protecting group on the baccatin core II and then deprotecting the protecting group after sidechain attachment. 
The selective deesterification of taxanes at the C-10 position via hydrazinolysis has been published: Datta, Apurba; Hepperle, Michael; Georg, Gunda I. Selective Deesterification Studies on Taxanes: Simple and Efficient Hydrazinolysis of C-10 and C-13 Ester Functionalities. J. Org. Chem. (1995), 60(3), 761-3. An alternate reference in the literature describes the use of basic hydrogen peroxide with similar results.
Several references for the prepartion of C-10 analogs have appeared in the art and these are, Holton, Robert A.; Chai, Ki Byung. C-10 Taxane derivatives and pharmaceutical compositions containing them as antileukemia and antitumor agents. PCT Int. Appl. 60 pp WO 9415599 Jul. 21, 1994.
Rao, K. V.; Bhakuni, R. S.; Oruganti, R. S. J. Med. Chem. 1995 38, 3411-3414.
Kant, J.; O""Keeffe, W. S.; Chen, S-H.; Farina, V.; Fairchild, C.; Johnston, K.; Kadow, J. F; Long, B. H.; Vyas, D. A. Tetrahedron Letts. 1994, 35, 5543-5546.
Ojima, I.; Slater, J. C.; Michaud, E.; Kuduk, S. D.; Bounaud, P-Y.; Vrignaud, P.; Bissery, M-C.; Veith, J. M. Pera, P. Bernacki. R. J. J. Med. Chem. 1996, 39, 3889-3896.
Using the methodology described in Scheme III or the abovementioned art, C-10 substituents covered by this invention were installed. A base is normally required in Step (L) to initially deprotonate a proton from C-10 hydroxy group. A particularly useful base for Step (a) is a strong base such as C1-6alkyllithium, lithium bis(trimethylsily)amide, or the like base used in about 1.1 equivalent amount. The deprotonation by base is preferably conducted in aprotic solvent, such as tetrahydrofuran, at low temperature, usually in the range from xe2x88x9240xc2x0 to 0xc2x0 C. The substituents are attached to the C-10 deprotonated hydroxyl group (alkoxide)in step L using RfC(O)Cl or the corresponding acid bromide or anhydride. Compounds III are then converted to I by the methodology described previously.
An alternative preparation of compounds I is depicted in Scheme IV. The preparation of the amine intermediate VI is described in the examples and is carried out by methodology which is well known in the art. The amine intermediate VI is dissolved in an inert solvent such as ethyl acetate and a base such as sodium bicarbonate is added. A stoichiometric or slightly greater amount of most preferably an acid chloride or alternatively acid anhydride is added to provide compound I directly. 
The specific examples that follow illustrate the syntheses of the compounds of the instant invention, and is not to be construed as limiting the invention in sphere or scope. The method may be adapted to variations in order to produce the compound embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compound in somewhat different manner will also be evident to one skilled in the art.
In the following experimental procedures, all temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (d) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). The solvents employed for taking NMR spectra are acetone-d6 (deuterated acetone). DMSO-d6 (perdeuterodimethylsulfoxide), D2O (deuterated water), CDCl3 (deuterochloroform) and other conventional deuterated solvents. The infrared (IR) spectral description include only absorption wave numbers (cmxe2x88x921) having functional group identification value
Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth.
Silica gel used in the following experimentals is silica gel 60 with a particle size 230-400 mesh obtained from EM Separations Technology.
The abbreviations used herein are conventional abbreviations widely employed in the art. Some of which are: DAB (deacetylbaccatin III); MS (mass spectrometry); HRMS (high resolution mass spectrometry); Ac (acetyl); Ph (phenyl); v/v (volume/volume); FAB (fast atom bombardment); NOBA (m-nitrobenzyl alcohol); min (minute(s)); h or hr(s) (hour(s)); DCC (1,3-dicyclohexylcarbodiimide); BOC (t-butoxycarbonyl); CBZ or Cbz (benzyloxycarbonyl); Bn (benzyl); Bz (benzoyl); Troc (2,2,2-trichloroethyloxycarbonyl), DMS (dimethylsilyl), TBAF (tetrabutylammonium fluoride), DMAP (4-dimethylaminopyridine); TES (triethylsilyl); DMSO (dimethylsulfoxide); THF (tetrahydrofuran); HMDS (hexamethyidisilazane); MeOTf (methyltriflate); NMO (morpholine-N-oxide); (DHQ)2PHAL (hydroquinine 1,4-phthalazinediyl diether). Tf=triflate=trifluoromethanesulfonate; LRMS (low resolution mass spectrometry); ESI (electrospray ionization); TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical); DBU (diazobicycloundecene); MOMCl (chloromethyl methyl ether); Ac (acetyl); (Ar, aryl); Bz (benzoyl); Cbz (benzyloxycarbonyl); DCI (desorption chemical ionization); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); FAB (fast atom bombardment); H (hour(s)); HRMS (high resolution mass spectrometry); LiHMDS (lithium hexamethyidisilazane or lithium bis(trimethylsilyl)amide); HMDS (hexamethyldisilazane); i-PrOH (isopropylalcohol): min (minute(s)); MS (mass spectrometry); Ph (phenyl); rt (room temperature); tBu (tertiarybutyl); TES (triethylsilyl), THF (tetrahydrofuran)TLC (thin layer chromatography) Y (yield) TPAP (tetrapropyl ammonium peruthenate); MCPBA (meta chloroperoxy benzoic acid); LDA (lithium diisopropyl amide); DMF (dimethylformamide); TBS (tert-butyl-dimethylsilyl); 18-crown-6 (1, 4, 7, 10, 13, 16-hexaoxacyclo-octadecane); DEAD (diethylazodicarboxylate).